PROJECT SUMMARY Epilepsy is a common neurological disorder that affects 50 million people worldwide. Approximately 30% of epileptic patients have treatment resistant (refractory) seizures, thereby presenting a major clinical challenge and burden. Temporal lobe epilepsy (TLE) is the most common form of refractory human epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common form of TLE. Approximately 20% of patients with MTLE fail to achieve adequate seizure control. MTLE is characterized by spontaneous seizures, hippocampal sclerosis, and neuropsychological deficits. At present, surgical resection of the epilepsy focus is the best treatment strategy for this disorder; however, this procedure is only used in a subset of cases. Consequently, there is a need to develop alternative treatments that can effectively mitigate the broad spectrum of clinical features associated with MTLE, while minimizing unwanted side effects. Reversible acetylcholinesterase inhibitors (rAChEIs) (e.g., Huperzine A and donepezil) are most widely used in the treatment of dementia and Alzheimer's disease; however, there is increasing evidence that this class of compounds might be therapeutic in the treatment of epilepsy. Recently published data from our group demonstrated that the Huperzine A provides robust and sustained protection against induced seizures in a mouse model of the catastrophic, treatment-resistant encephalopathy Dravet syndrome (DS). In addition, we now provide preliminary data demonstrating 1) that donepezil can also increase resistance to induced seizures in the DS model, and 2) that Hup A dramatically reduces spontaneous seizure development in the intra- hippocampal kainic acid (IH-KA) mouse model of MTLE. Based on these observations, and the ability of rAChEIs to also protect against inflammation and cell death, and promote neurogenesis, we hypothesize that this class of compounds will be particularly efficacious in the treatment of MTLE. We will test this hypothesis by evaluating and comparing the ability of Hup A and donepezil to reduce spontaneous seizure frequency and severity (Aim 1) and ameliorate behavioral abnormalities and neuron loss (Aim 2) in the IH-KA mouse model of MTLE. This study will also have broader implications for the treatment of other forms of refractory epilepsy.